Abstract
The human ether-&x00E0;-go-go-1 (h-eag1) voltage-dependent K+ channel is necessary for cell cycle progression and its overexpression stimulates tumorigenesis; specific inhibition of h-eag1 expression leads to a reduction in tumor cell proliferation in vitro and in vivo. On the other hand, the tumor-suppressor gene p53 and its downstream genes consist of a complex molecular signaling network and p53 is at the center of this network regulating diverse physiological responses to cancer-related stresses. We report here that h-eag1 expression is controlled by the p53&x2212;miR-34&x2212;E2F1 pathway through a negative feed-forward mechanism. We first established E2F1 as a transactivator of h-eag1 gene. We then revealed that miR-34, a known transcriptional target of p53, is an important negative regulator of h-eag1 through dual mechanisms by directly repressing h-eag1 at the post-transcriptional level and indirectly silencing h-eag1 at the transcriptional level via repressing E2F1. The antisense against h-eag1 antagonized the growth-stimulating effects and the upregulation of h-eag1 expression in SHSY5Y cells, induced by E2F1 overexpression, inhibition of p53 activity, or knockdown of miR-34. Thus, negative regulation of p53 causes oncogenic overexpression of h-eag1 by relieving the negative feed-forward regulation of the p53&x2212;miR-34&x2212;E2F1 pathway or overexpression of h-eag1 fulfills the oncogenic cell growth-stimulating effect of p53 inactivation.
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Wang, Z., Chen, C., Li, Z. et al. EAG K+ channel joins the p53&x2212;miR-34&x2212;E2F1 signaling pathway as a terminal effecter component for its oncogenic overexpression and action. Nat Prec (2010). https://doi.org/10.1038/npre.2010.4507.1
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DOI: https://doi.org/10.1038/npre.2010.4507.1